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Ageing Research Reviews 42 (2018) 40–55

Contents lists available at ScienceDirect

Ageing Research Reviews

journal homepage: www.elsevier.com/locate/arr


Poor cognitive ageing: Vulnerabilities, mechanisms and the impact of T

nutritional interventions
Sophie Miquela, Claire Champb, Jon Dayc, Esther Aartsd, Ben A. Bahre, Martijntje Bakkerf,
Diána Bánátig, Vittorio Calabreseh, Tommy Cederholmi, John Cryanj, Louise Dyeb,
Jonathan A. Farrimondk, Aniko Korosil, Sophie Layém, Stuart Maudsleyn, Dragan Milenkovico,p,
M.Hasan Mohajeriq, John Sijbenr, Alina Solomons, Jeremy P.E. Spencert, Sandrine Thuretu,
Wim Vanden Berghev, David Vauzourw, Bruno Vellasx, Keith Wesnesy,z,A,B,C, Peter WillattsD,

Raphael WittenbergE, Lucie Geurtsg,
Mars-Wrigley, 1132 W. Blackhawk Street, Chicago, IL 60642, United States
Human Appetite Research Unit, School of Psychology, University of Leeds, Leeds, LS2 9JT, United Kingdom
Cerebrus Associates Limited, The White House, 2 Meadrow, Godalming, Surrey, GU7 3HN, United Kingdom
Donders Institute for Brain, Cognition, and Behaviour, Radboud University Nijmegen, Kapittelweg 29, 6525 EN Nijmegen, The Netherlands
Biotechnology Research and Training Centre, University of North Carolina – Pembroke, United States
The Netherlands Organisation for Health Research and Development, Laan van Nieuw Oost-Indië 334, 2593 CE The Hague, The Netherlands
International Life Sciences Institute, Europe (ILSI Europe), Av E. Mounier 83, Box 6, 1200 Brussels, Belgium
University of Catania, Department of Biomedical and Biotechnological Sciences, Biological Tower – Via Santa Sofia, 97, Catania, Italy
University of Uppsala, Institutionen för folkhälso- och vårdvetenskap, Klinisk nutrition och metabolism, Uppsala Science Park, 751 85 Uppsala, Sweden
Anatomy & Neuroscience, University College Cork, 386 Western Gateway Building, Cork, Ireland
Lucozade Ribena Suntory Ltd., Uxbridge, United Kingdom
Swammerdam Institute for Life Sciences, Center for Neuroscience, University of Amsterdam, Science Park 904, 1098 XH, Amsterdam, The Netherlands
Nutrition et Neurobiologie Intégrée, INRA Bordeaux University, 146 rue Léo Saignat, 33076 Bordeaux cedex, France
Department of Biomedical Research and VIB-UAntwerp Center for Molecular Neurology, University of Antwerp, Gebouw V, Campus Drie Eiken, Universiteitsplein 1, 2610
Antwerpen, Belgium
INRA, Human Nutrition Unit, UCA, F-63003, Clermont-Ferrand, France
Department of Internal Medicine, Division of Cardiovascular Medicine, School of Medicine, University of California Davis, Davis, CA 95616, United States
DSM Nutritional Products Ltd., Wurmisweg 576, Kaiseraugst 4303, Switzerland
Nutricia Research, Nutricia Advanced Medical Nutrition, PO Box 80141, 3508TC, Utrecht, The Netherlands
Aging Research Center, Karolinska Institutet, Gävlegatan 16, SE-113 30 Stockholm, Sweden
Hugh Sinclair Unit of Human Nutrition and Institute for Cardiovascular and Metabolic Research, Department of Food and Nutritional Sciences, University of Reading,
Whiteknights, Reading, RG6 6AP, United Kingdom
Institute of Psychiatry, Psychology and Neuroscience, King’s College London, The Maurice Wohl Clinical Neuroscience Institute,125 Coldharbour Lane, SE5 9NU London,
United Kingdom
PPES, Department Biomedical Sciences, University Antwerp, Campus Drie Eiken, Universiteitsplein 1, 2610 Antwerp, Belgium
University of East Anglia, Norwich Research Park, Norwich NR4 7TJ, United Kingdom
Department of Geriatric Medicine, CHU Toulouse, Gerontopole, Toulouse, France
Wesnes Cognition Limited, Little Paddock, Streatley on Thames, RG8 9RD, United Kingdom
Medical School, University of Exeter, Exeter, United Kingdom
Department of Psychology, Northumbria University, Newcastle, United Kingdom
Centre for Human Psychopharmacology, Swinburne University, Melbourne, Australia
Medicinal Plant Research Group, Newcastle University, United Kingdom
School of Psychology, University of Dundee Nethergate, Dundee, DD1 4HN, United Kingdom
London School of Economics and Political Science, Personal Social Services Research Unit, London, United Kingdom


Keywords: Background: Ageing is a highly complex process marked by a temporal cascade of events, which promote al-
Cognition terations in the normal functioning of an individual organism. The triggers of normal brain ageing are not well
Preventive diet understood, even less so the factors which initiate and steer the neuronal degeneration, which underpin dis-
Cognitive decline orders such as dementia. A wealth of data on how nutrients and diets may support cognitive function and

Correspondning author at: International Life Sciences Institute, Europe (ILSI Europe), Av E. Mounier 83, Box 6, Brussels 1200, Belgium.
E-mail address: publications@ilsieurope.be (L. Geurts).

Received 8 August 2017; Received in revised form 8 December 2017; Accepted 8 December 2017
Available online 15 December 2017
1568-1637/ © 2017 The Authors. Published by Elsevier B.V. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/BY-NC-ND/4.0/).
S. Miquel et al. Ageing Research Reviews 42 (2018) 40–55

Neuro-inflammation preserve brain health are available, yet the molecular mechanisms underlying their biological action in both
Plant-food bioactives normal ageing, age-related cognitive decline, and in the development of neurodegenerative disorders have not
been clearly elucidated.
Objectives: This review aims to summarise the current state of knowledge of vulnerabilities that predispose
towards dysfunctional brain ageing, highlight potential protective mechanisms, and discuss dietary interventions
that may be used as therapies. A special focus of this paper is on the impact of nutrition on neuroprotection and
the underlying molecular mechanisms, and this focus reflects the discussions held during the 2nd workshop
‘Nutrition for the Ageing Brain: Functional Aspects and Mechanisms’ in Copenhagen in June 2016. The present
review is the most recent in a series produced by the Nutrition and Mental Performance Task Force under the
auspice of the International Life Sciences Institute Europe (ILSI Europe).
Conclusion: Coupling studies of cognitive ageing with studies investigating the effect of nutrition and dietary
interventions as strategies targeting specific mechanisms, such as neurogenesis, protein clearance, inflammation,
and non-coding and microRNAs is of high value. Future research on the impact of nutrition on cognitive ageing
will need to adopt a longitudinal approach and multimodal nutritional interventions will likely need to be
imposed in early-life to observe significant impact in older age.

1. Introduction ageing, highlight potential protective mechanisms and how dietary

interventions can be a strategy to target some of these mechanisms, and
By 2030, the number of people aged 60 years or over is predicted to address future research priorities to ameliorate the effects of brain
grow by 56% from 901 million to 1.4 billion (United Nations ageing. This review focuses on molecular mechanisms including the
Department of Economic and Social Affairs, 2015). By 2050, the like- novel angles covered by the workshop.
lihood of developing neurodegenerative diseases, such as Alzheimer’s
or vascular dementia (VD) will increase by 45% (Alzheimer’s, 2015). As 2. Vulnerabilities associated with poor cognitive ageing
a result, all nations will need to divert an increasing proportion of their
healthcare funding to treat and manage dementia and other age-related 2.1. Early-life stress
cognitive diseases. It is predicted that by 2050, increases in the ageing
population will present significant economic and social challenges and Research with humans and animals has demonstrated that the brain
the burden for healthcare systems and on society will become en- is sensitive to stress and is especially vulnerable during early childhood
ormous. The current cost of dementia alone is €725 billion worldwide and old age (Benton, 2010; Jane Costello et al., 2007; Maselko et al.,
and is expected to reach €1,7 trillion by 2030 (Alzheimer’s Disease 2011; Nelson and Trainor, 2007; Walker et al., 2000). Exposure to
International and International, 2015). The costs of dementia care are early-life stress (ES) is associated with lasting changes in the structure
very substantial, and a large proportion of the costs also fall to unpaid of the adult brain and accelerated cognitive decline. A possible role for
carers. The value concerning loss of quality of life of people with de- epigenetic mechanisms, involving DNA methylation changes has been
mentia needs to be considered in addition to the costs of care. suggested, although the underlying molecular mechanisms remain lar-
To address this major global challenge, research funding and effort gely unknown (Bale, 2015; Blouin et al., 2016; Sheerin et al., 2017;
has increasingly focused on the mechanisms associated with brain Weaver et al., 2004; Yao et al., 2016). Animal studies impose ES using
ageing and cognitive decline. The number of publications studying interventions, such as limited access to nest and bedding material
cognitive decline is currently around 16,000, and this growing body of (Molet et al., 2014; Naninck et al., 2015). Such interventions are
research is increasing rapidly, as scientists and governments seek to thought to mimic important aspects of human chronic ES and are
identify solutions to the coming challenges. considered valuable tools to investigate the mechanisms linking ac-
There is overwhelming evidence that major aspects of cognitive celerated cognitive decline with ES. So far, the lasting effects of ES on
function decline from early adulthood onwards, even in cognitively cognition have been attributed mostly to alterations in maternal care
healthy individuals (Salthouse, 2010; Salthouse, 2012a,b). This decline and neuroendocrine factors (Naninck et al., 2015; Teicher et al., 2012),
starts during the third decade of life, affects many dimensions of cog- while the role of early nutrition has been largely ignored. However,
nitive function, and occurs in all individuals (Salthouse, 2010). There both ES and early-life malnutrition often occur simultaneously, and it
are two major stages to healthy brain ageing, first maturation and de- may be important to investigate the separate and interactive con-
velopment to adulthood, and second the maintenance of function from sequences for cognition (Naninck et al., 2013). If early-life nutrition is
adulthood to old age (Salthouse, 2010; Salthouse, 2012a,b). Cognitive involved in mediating ES effects on brain structure and function, it is
function tends to improve over the first 18 years of life, peak during the likely that the lasting effects of ES result from the synergistic action of:
next few years, and then deteriorate steadily thereafter (Salthouse, 1) the quality and quantity of early nutrition 2) stress hormones and 3)
2010; Salthouse, 2012a,b). In the absence of adequate nutrition or in sensory stimuli from the mother (Lucassen et al., 2013). Therefore, it is
the presence of a variety of disease states, cognitive function in ‘healthy’ important to study if (and how) ES alters the nutritional/metabolic
individuals will be detrimentally perturbed during their lifetime. Most environment in both the mother and her offspring. Such an integrated
people will encounter disease at some stage of their life, with the ma- approach provides new opportunities for devising nutritional inter-
jority of diseases associated with some form of negative consequences vention strategies that prevent enduring effects of ES on mental health.
for cognitive function (Wesnes, 2006). However, evidence is accumu- As ES exposure often cannot be prevented, a deeper understanding of
lating that cognitive decline during normal ageing can be attenuated by all elements involved in early programming of the brain by ES is re-
a wide variety of factors, such as improved nutrition, appropriate quired to develop novel treatment strategies to protect vulnerable in-
dietary supplementation, increased physical exercise, and the perfor- dividuals from the lasting effects of ES. The effects of various elements
mance of mental exercises (Barberger-Gateau, 2014; Ferreira et al., of the early-life environment (e.g. maternal care, neuro-endocrine fac-
2015; Gupta, 2016; Makin, 2016; McGilvray, 2016). tors, nutrient availability, and metabolic hormones) are often con-
In 2016, the ILSI Europe’s Nutrition and Mental Performance Task sidered in isolation, despite the intense crosstalk between stress and
Force organised the 2nd workshop in a series on ‘Nutrition for the metabolic programming. However, emerging evidence demonstrates
Ageing Brain’. To capture the value of this workshop, the aim of this that enriching the diet early in life with essential micronutrients pre-
paper is to review the vulnerabilities associated with poor cognitive vents some of the negative consequences of ES, opening new

S. Miquel et al. Ageing Research Reviews 42 (2018) 40–55

perspectives for nutritional interventions (Naninck et al., 2017). had significantly lower levels of brain-derived neurotrophic factor
(BDNF) in the cortex and hippocampus to that of SPF mice (Sudo et al.,
2.2. Gut microbiome 2004). Similarly, microbial colonisation has been suggested to initiate
signalling mechanisms that influence neural circuits, which modulate
Early-life stress in animals results in changes in the microbiome in motor control and anxiety-like behaviours. Specifically, germ-free mice
adulthood (O’Mahony et al., 2009). Specific changes in the stress re- showed greater motor activity and reduced anxiety when compared to
sponse are linked to changes in the functioning of the gut-brain axis SPF mice with a normal gut microbiota (Heijtz et al., 2011). Moreover,
(Dinan and Cryan, 2013). Furthermore, there is evidence of co-mor- as well as displaying reduced anxiety-like behaviour, germ-free mice
bidity between gastrointestinal conditions and stress-related psychiatric have also shown increased explorative behaviour in comparison to SPF
symptoms (Kennedy et al., 2012). mice (Neufeld et al., 2011). Interestingly, the microbiome has been
The gut microbiota influences development and homeostasis in found to influence neural circuits in a gender-dependent manner. In
adulthood (Claesson et al., 2012). Unlike healthy adults, the composi- male germ-free animals, a significant increase in hippocampal serotonin
tion of the intestinal microbiota of those aged above 65 shows more levels, 5-hydroxyindoleacetic acid, and plasma concentrations of tryp-
inter-individual variation (Biagi et al., 2010; Claesson et al., 2011). The tophan were identified relative to conventionally colonised control
microbiota profiles of ageing individuals have been associated with the animals. The elevated serotonin and 5-hydroxyindoleacetic acid con-
degree of retention of a core microbiome, long-term residential care, centrations were not influenced by colonisation post-weaning, regard-
and age and habitual diet (O’Toole and Jeffery, 2015). The composition less of tryptophan levels returning to baseline values. As such, the lack
of faecal microbiota in the elderly has also been found to correlate with of a normal gut microbiome has long-term consequences for central
frailty and co-morbidity (Claesson et al., 2012). Specifically, the gut nervous system neurotransmission, which cannot be restored following
microbiota has been shown to modulate the gut-brain axis, through the introduction of a normal gut microbiome in later life (Clarke et al.,
which it exerts an influence on both cognitive function and plasticity 2013). Conversely, there was greater down-regulation of genes related
during ageing (Leung et al., 2015). to the immune system (Stilling et al., 2015), which supports the sug-
Differences in the microbiota of young and adult mice fed a control gestion that germ-free mice have an under-developed immune system
diet have been found to influence social behaviour (Palma et al., 2014). (Cebra, 1999). Amygdala transcriptome alterations failed to be com-
In a series of behavioural experiments, young mice showed significantly pletely restored following colonisation with conventional microbiota
elevated exploratory behaviour of a displaced object relative to aged post-weaning, thus lending further support towards hypotheses invol-
mice, and aged mice explored the open arms of a maze significantly less ving the existence of critical stages of neuro-development (Stilling
than young mice. Furthermore, young mice demonstrated significantly et al., 2015). Likewise, both germ-free mice and those colonised post-
greater exploration of a novel mouse compared to aged mice in a social weaning have been found to have 190 and 15 genes differentially ex-
recognition experiment (Desbonnet et al., 2014; Heijtz et al., 2011). pressed in the prefrontal cortex relative to conventionally colonised
Ageing has also been associated with an increase in gut permeability. mice, respectively; with significant overlap suggesting the absence of
Oral administration of fluorophores-conjugated macromolecules (i.e. microbiota during early development has irreversible consequences for
fluorescein isothiocyanate-dextran) in young and aged mice has shown cellular functions. In particular, 19% and 27% of genes found to be up-
that aged mice have significantly greater gut permeability, especially regulated in both mice types were associated with myelin components
following restraint stress. Moreover, the presence of proinflammatory or neuronal activity, respectively.
cytokines is significantly greater in the plasma of aged mice relative to
young mice, thus showing an increased pro-inflammatory profile in 2.3. Non-communicable diseases, such as obesity, type 2 diabetes and
ageing (Scott et al., 2017). Work with invertebrates has highlighted the glucose regulation
role of the microbiota in directly and indirectly impacting the host
genome to promote longevity. For example, worms consuming met- In contrast to some infectious diseases, non-communicable diseases,
formin have an increased lifespan in an AMPK-dependent manner. This such as neurodegenerative disease, cancer, obesity, and cardiometa-
relationship is indirectly mediated by the impact of metformin on bolic disorders do not typically develop rapidly, but rather progress to a
bacterial folate metabolism (Heintz and Mair, 2014). pathological state over many years. Obesity is associated with co-
Germ-free animals have been used to elucidate the relationship morbidities, such as chronic inflammation, impaired glucose tolerance,
between gut microbiota and pathological ageing. A germ-free mouse insulin resistance, and type 2 diabetes mellitus (T2DM), and rates of
model of Alzheimer’s disease (AD) was found to show a reduced obesity are increasing. Midlife obesity is a significant risk factor for
number of β-amyloid plaques relative to control AD mice with intestinal later life dementia (Sellbom and Gunstad, 2012), and has been found to
microbiota. However, the presence of plaques in the germ-free mice be associated with cognitive impairment across a range of cognitive
increased dramatically following the introduction of microbiota har- domains in a recent systematic review (Prickett et al., 2015). However,
vested from the control mice (Harach et al., 2015). Germ-free mice in older adults, current obesity levels have been inversely associated
models are valuable in illustrating the importance of gut microbiota in with dementia (Fitzpatrick et al., 2009). This could represent an
the gut-brain relationship. Research has shown that gut microbiota is “obesity paradox” in which late life weight loss may precede dementia
required for normal stress-hormone signalling, neural function, in- (Hughes et al., 2009) and occur before a presentation of cognitive im-
cluding increased hippocampal neurogenesis, increased blood-brain pairment. A recent retrospective cohort study of almost 2 million in-
barrier permeability, regulating immune function, and anxiety-like and dividuals aged over 40 years in the UK reported that being underweight
sociability behaviours (Luczynski et al., 2016). Further, postnatal mi- in middle age and old age carries an increased risk of dementia
crobial colonisation has been implicated in brain plasticity and the (Qizilbash et al., 2015). However, this is controversial and in contrast to
Hypothalamic Pituitary-Adrenal (HPA) stress reaction of germ-free and the evidence of an association between obesity and dementia. This
specific pathogen-free (SPF) mice. Following 1 h of restraint stress, finding may therefore reflect the possible tendency to underdiagnose
germ-free mice had markedly higher plasma adrenocorticotropic hor- dementia by general practitioners at the time the data was collected,
mone (ACTH) and corticosterone levels relative to SPF mice (Sudo and over or under adjustment for a number of factors, such as com-
et al., 2004). This HPA response in germ-free mice was partially cor- peting risk of mortality, selection bias, and bias in the diagnosis of
rected three weeks following reconstitution of SPF faeces at 9 weeks of dementia in those with lower BMI/age (Harrison and Shenkin, 2015).
age but not at 17 weeks, indicating that microbial colonisation at an Obesity may impact cognitive function prior to any dementia-re-
early stage of development is needed for the HPA system to become lated cognitive decline, leading to the suggestion that interventions
fully susceptible to inhibitory neural modulation. Germ-free mice also aimed at promoting weight loss may attenuate late-life cognitive

S. Miquel et al. Ageing Research Reviews 42 (2018) 40–55

decline. Midlife obesity is most consistently associated with impaired 2.4. Environmental factors and epigenetic modulation
executive function in older adults, but impairments in language, motor,
and memory performance have also been documented (Gunstad et al., Adipocytes release pro-inflammatory adipokines, which can pro-
2010). A number of mechanisms have been proposed to account for the mote the pathological chronic inflammation associated with obesity.
association between obesity and impairment of cognitive function. Epigenetic ageing can be accelerated by the cumulative addition of
These include inflammation, impaired cerebral metabolism or blood chemical DNA methylation marks to the (epi)genome (Quach et al.,
flow, elevated leptin, and neuronal degradation. Inflammatory markers 2017). As such, an individual’s personal lifestyle (stress, diet, pollution,
such as C-reactive protein (CRP) are found in the obese, where greater exercise, smoking, alcohol consumption, and sleep deprivation) leaves a
brain atrophy, lower grey matter and total brain volume, and increased trail of chemical epigenetic marks in the genome by means of cumu-
white matter hyperintensities have also been observed (Prickett et al., lative (stochastic) DNA methylation, which alters gene expression,
2015). Other mechanisms suggested to account for obesity-related im- leading to a spectrum of disease/health related phenotypes. An un-
pairment of cognitive function relate to the co-morbidities, which are healthy lifestyle will accelerate an individual’s epigenetic age (clock)
common in obese adults and apparent usually from midlife, for example (Mather et al., 2016; Nevalainen et al., 2017; Quach et al., 2017;
hypertension, dyslipidemia, impaired glucose tolerance, insulin re- Zannas et al., 2015) as compared to their biological age, and promote
sistance, and T2DM. early onset of complex lifestyle diseases, such as cancer, cardiometa-
The association between diabetes and cognitive impairment was bolic diseases, and cognitive decline (Fraga et al., 2005; Wolf et al.,
recognised almost a century ago (Miles and Root, 1922). Numerous 2016). In contrast, a healthy lifestyle will decrease epigenetic age
studies have compared cognitive functioning in diabetic patients with (clock) relative to biological age and delay the onset of lifestyle disease
non-diabetic controls (Brands et al., 2005). The majority of these stu- (i.e. healthy years free of disease are added). Epigenetic ageing can be
dies detail cognitive impairments, such as decreased performance on compared to the emptying of an hourglass, where lifestyle determines
attention and memory tasks (Awad et al., 2004; Brands et al., 2004; the speed at which sand moves from the top to the lower compartment
Lamport et al., 2013; Tun et al., 1990; van den Berg et al., 2009). (reflecting metabolic inflammatory rate). This may also explain the
Performance of complex cognitive tasks appears to be more impaired as rather small epigenetic impact of relatively short (6–8 weeks) diet in-
a result of diabetes, whereas performance of less demanding tasks terventions in comparison to the epigenetic impact of chronic disease
seems to be comparable to controls (Tun et al., 1990). This pattern promoting lifestyle conditions/exposure, which typically are persistent
parallels the cognitive changes of normal ageing, where age differences over many years (smoking, stress, pollution, alcohol abuse) (Milenkovic
are insignificant on less demanding immediate memory tasks, but more et al., 2014). Moreover, nutrition and exercise interventions trigger
pronounced on secondary or long-term memory tasks (Perlmuter et al., highly variable (epigenetic) DNA methylation changes involved in
1984). vascular inflammation, cardio-metabolic, cognitive health, and epige-
Impaired glucose tolerance (IGT) often occurs prior to the devel- netic age (Quach et al., 2017). Epigenetic variation creates multiple
opment of diabetes and may contribute to cognitive impairments redundant possibilities (homeostasis) to achieve healthy ageing or to
(Lamport et al., 2009). Recent studies have shown that the performance develop premature ageing/lifestyle diseases. Inter-individual variation
of ostensibly healthy middle-aged women with IGT was impaired in in microbiome composition contributes in different pharmacodynamics
cognitive tasks which predominantly engage the hippocampus of nutritional bioactives (Cortese et al., 2016; Paul et al., 2015; Stilling
(Lamport et al., 2014). Interventions that improve glucose tolerance et al., 2014). Inter-individual epigenetic variation in expression of
have also been shown to improve cognitive function (Yamamoto et al., ADME proteins (involved in absorption, distribution, metabolism, and
2009). excretion) further contributes to inter-individual variation through
Since obesity and subsequent T2DM increases the risk of AD by 65% different pharmacodynamics of nutritional bioactives (Fisel et al., 2016;
(relative risk in T2DM is 1.46 (Cheng et al., 2012)), and around 80% of Ingelman-Sundberg and Cascorbi, 2016). Finally, the inter-individual
AD patients have problems with glycaemic control, AD has been re- epigenetic nutritional response is also co-determined by genetic single
ferred to as Type 3 diabetes (De La Monte and Wands, 2008). It has nucleotide polymorphisms (SNPs) in genes associated with methyl (one
been proposed that AD is a metabolic disease, mediated by impairments carbon) donor metabolism, i.e. methylenetetrahydrofolate reductase
in brain insulin responsiveness, glucose utilisation, and energy meta- (Anderson et al., 2012; Declerck et al., 2017; Friso et al., 2002;
bolism, which leads to increased oxidative stress and inflammation, Quinlivan et al., 2005; Stover, 2009).
which worsens insulin resistance (De La Monte and Wands, 2008).
Advanced glycation end-products (AGEs) are also elevated in both 3. Potential mechanisms underlying vulnerabilities
T2DM and AD. The relative risk of VD in those with T2DM is 2.49
(Cheng et al., 2012), and its development relates to a history of hy- 3.1. Neurogenesis
pertension and disturbances in cerebral blood flow. Metabolic dis-
turbances, such as insulin resistance, hyperlipidaemia, cholester- The hippocampus is a key brain structure associated with learning,
olaemia, and impaired vascular function (e.g. increased blood pressure memory, and mood, and is one of the two structures in the adult brain
and reduced cerebral blood flow), which occur at sub-clinical levels in where the formation of new neurons (or neurogenesis) persists
pre-disease states, may elevate the risk of subsequent cognitive decline throughout life in numerous species, including in human (Eriksson
and dementia (Hassing et al., 2009). Evidence from MRI studies sug- et al., 1998; Ernst et al., 2014; Spalding et al., 2013). The functionality
gests that asymptomatic cerebrovascular brain injury is common, often of these adult-born neurons in the adult hippocampus has been linked
occurring in midlife and related to cardiovascular disease risk factors. directly to cognition, learning, and memory (Deng et al., 2010; Eisch
This implies that interventions that address cerebrovascular risk factors and Petrik, 2012). For example, in the adult rodent, hippocampal
during middle age may be prophylactic for cognitive ageing. One such neurogenesis is crucial for pattern separation abilities (Clelland et al.,
intervention is bariatric surgery, which has been shown to promote 2009). Hippocampal neurogenesis decreases with age in rodents, as
rapid improvements in memory and executive function that persist for does pattern separation abilities in humans (and cognition in general).
several years postoperatively (Spitznagel et al., 2015). This post-op- Therefore, neurogenesis could be the target for interventions to prevent
erative improvement in memory performance is not seen in individuals or slow down cognitive ageing.
with a family history of AD (Alosco et al., 2014), which suggests that Adult hippocampal neurogenesis can be modulated by the systemic
genetic vulnerability or family history may attenuate cognitive recovery environment (blood) in an age-dependent manner (Murphy and Thuret,
post-bariatric surgery. 2015). Studies using heterochronic parabiosis, which involves the sur-
gical attachment of young to old organisms so they share a common

S. Miquel et al. Ageing Research Reviews 42 (2018) 40–55

vascular system, have revealed that the systemic environment has a associated synaptic pathology (Bendiske and Bahr, 2003; Butler et al.,
profound effect on stem cell function and hippocampal neurogenesis. In 2011; Lee et al., 2004). The autophagy-lysosomal system plays a critical
particular, specific youthful rejuvenating circulatory factors reverse role in protein clearance and neuronal homeostasis (Bahr et al., 2012;
age-related declines in stem cell function and restore neurogenesis and Bendiske et al., 2002; Bendiske and Bahr, 2003; Mueller-Steiner et al.,
some associated hippocampal memory tasks, whereas the old milieu 2006), affording efficient protein digestion and turnover and con-
contains inhibitory factors that impede stem cell function and neuro- tributing to cell health and possibly longevity (Folick et al., 2015).
genesis when transferred to young animals (Villeda et al., 2014, 2011; Lysosomal enzymes such as cathepsin B represent therapeutic targets
Villeda and Wyss-Coray, 2013). for clearing age-related protein accumulations that lead to synaptic
Diet will impact on the composition of the systemic milieu and can pathology. An additional avenue to offset age-related proteostatic stress
similarly modulate stem cell ageing, adult hippocampal neurogenesis, has been suggested to be through blocking the extralysosomal enzyme
and cognition (Murphy and Thuret, 2015). Therefore, modulation of calpain, leading to both induction of autophagy and positive protea-
adult hippocampal neurogenesis by diet emerges as a possible me- somal regulation (see (Romine et al., 2017)).
chanism by which nutrition can impact on cognitive ageing either via The lysosomal protease, cathepsin B, responds to age-related protein
the systemic milieu or via the gut-microbiota, as discussed earlier. accumulation stress (Bahr, 2009; Bendiske and Bahr, 2003), perhaps as
Given that both age and diet can alter stem cell function and neuro- a compensatory response that accounts for the gradual nature of disease
genesis, and that these alterations are facilitated by changes in the le- progression in most AD cases. Cathepsin B has been linked to tau
vels of circulating factors, these influences should be investigated fur- clearance (Farizatto et al., 2017), has been shown to degrade Aβ42
ther. Dietary interventions that potentially could promote healthy through carboxy-terminal truncation, and to correspondingly reduce Aβ
ageing by enhancing stem cell function and neurogenesis are discussed synaptic toxicity and neuropathology in transgenic mouse models and a
further below. There is now a need for dietary human interventions to hippocampal slice model (Bahr et al., 2012; Butler et al., 2011; Mueller-
assess specific neurogenesis-dependent cognitive tasks such as pattern Steiner et al., 2006; Wang et al., 2012). Exercise, which is thought to
separation. reduce the risk of AD, heart disease and other disorders, has recently
been shown to elevate cathepsin B in monkeys and humans, and the
3.2. Proteostasis and multi-dimensional controllers of ageing elevated levels also correlate with improved hippocampal-dependent
memory (Moon et al., 2016). Taken together, this is consistent with
In the early stages of brain ageing, neurons experience an imbalance research suggesting that exercise may reduce age-related memory loss
between protein production and protein clearance, which very likely and prevent or delay AD. In addition, enhancing lysosomal function has
increases the risk of age-related protein accumulation pathology linked been implicated as a strategy against α-synucleinopathy of PD and
to AD, Parkinson’s disease (PD), Huntington’s disease (HD), fronto- Lewy body diseases (Lee et al., 2004). In relation to HD, enhancing
temporal dementia (FTD), and other dementias (Bahr, 2009; Ross and cathepsins B and D was found to protect against mutant Huntington
Poirier, 2004; Wang et al., 2018). AD is the most common multi-pro- toxicity (Liang et al., 2011).
teinopathy, with phosphorylated tau and the Amyloid β42 (Aβ42) Further research to understand the importance of proteostasis is
peptide suspected as key pathogenic contributors (Glodzik-Sobanska recommended to identify positive modulators of the systems involved.
et al., 2009; Grundke-Iqbal et al., 1986). In 50–60% of AD cases, protein Positive cathepsin B modulators for reducing the risk of multi-protei-
accumulations also involve Tar-DNA binding protein-43 (TDP43), a nopathy may extend across synthetic and natural compounds. Efficient
protein linked to FTDs and amyotrophic lateral sclerosis, as well as α- clearance of age-related protein accumulations may require enhance-
synuclein, which accumulates in PD and related Lewy body diseases. ment of both proteasomal and lysosomal systems, thus future efforts are
Tau and Aβ42 pathology has been found to propagate across the elderly needed to understand the distinct interactions between the two clear-
brain in cognitively normal women and men, and their deposition is ance pathways in the brain (Farizatto et al., 2017) and to assess natural
associated with distinctive patterns of grey matter loss (Sepulcre et al., and synthesized agents for distinct and dual modulatory effects. Drugs
2016). Moreover, the two proteins were found to be associated with targeting only one type of pathogenic protein (Aβ42) have failed in
aberrant neural activity during memory encoding in cognitively healthy recent human trials for AD. However, a more hopeful outlook may be
older people, leading to declines in memory performance (Marks et al., provided by a compound that can target multiple proteins that accu-
2017). These studies broaden the concepts of cognitive ageing to il- mulate abnormally. While the usefulness of transgenic AD models for
lustrate that controlling AD-type protein accumulation events during screening potential therapeutics has been called into question in light of
ageing is important for the maintenance of mental performance in late- failed clinical trials, this issue reiterates the importance of taking into
life. account the multi-proteinopathy aspect of the disease. Transgenic mice
Strategies are needed to promote proteostasis in older age to control may be missing dozens or even thousands of human proteins to prop-
the synthesis, folding, trafficking, and clearance of aggregation-prone erly replicate human AD, which is something probably vastly different
proteins in order to reduce occurrences of synaptic compromise and than the disorders produced in mouse models. We may also never be
dementia risk. Such strategic avenues will likely need to target multiple able to adequately model human brain ageing or dementia for precise
pathogenic proteins to offset dementia-related accumulation events, drug-discovery efforts. For example, in a mouse’s short life, it is im-
often developing slowly for many years before memory problems arise. possible to reproduce the everyday human stress that can span several
Ubiquitously expressed chaperone proteins have been identified that decades. Many human genetic factors and protein–protein interactions
enable cells to cope with protein misfolding events, and the cellular may be involved in age-related cognitive decline. Targeting multiple
chaperones facilitate native folding and regulate the rates of protein aspects of early proteinopathy provides a potential strategy to promote
synthesis and clearance (Kalmar and Greensmith, 2017). Chaperone- cellular homeostasis and synaptic health for cognitive functions, per-
mediated autophagy degrades many types of proteins delivered to ly- haps through combinations of pro-lysosomal and pro-proteasomal nu-
sosomes and may attenuate proteinopathy and ageing (Loos et al., trition components. Promoting protein clearance pathways from middle
2017). Drug targets for proteostasis continue to be identified to: 1) age may be needed to effectively reduce the risk of age-related cogni-
induce chaperone levels and decrease the aggregation of diverse pro- tive impairment and extend the years with good mental performance
teins (Jimenez-Sanchez et al., 2015), 2) boost proteasomal protein for optimal benefit.
clearance activity to lower pathogenic tau levels, promote synaptic Ageing is a highly complex, pathophysiological process linking
maintenance, and improve cognitive performance (Farizatto et al., metabolic alterations to the generation of accumulated cellular/tissue
2017; Myeku et al., 2016), and 3) enhance enzymes of the autophagic- damage, and has been shown to underpin a wide variety of disorders
lysosomal pathway to reduce protein accumulation stress and associated with neurodegeneration (e.g. AD (Monacelli et al., 2017) and

S. Miquel et al. Ageing Research Reviews 42 (2018) 40–55

PD (Reeve et al., 2014), cardiovascular diseases (Ghebre et al., 2016), exogenous/endogenous stress, as discussed above, may be framed
and metabolic dysfunction (Brewer et al., 2016)). Highly complex within the context of hormesis, a dose response phenomenon, char-
processes such as ageing may be regulated by a small group of systems acterized by low-dose stimulation and high-dose inhibition. Numerous
controlling multidimensional protein factors named ‘hubs’ (Balistreri pharmacological agents and chemical stressors, when acting at low
et al., 2016; Chadwick et al., 2012; Korwitz et al., 2016; Morris, 2013). doses, are able to upregulate adaptive responses that protect against
Hub proteins connect multiple signalling protein ‘nodes’ within a larger subsequent noxious stimuli in a broad range of cellular conditions due
network. This ‘higher-level’ of network connectivity between hubs to normal and pathological ageing processes, as well as damage induced
greatly enhances the speed and fidelity of molecular coordination be- by exogenous agents, such as ionizing radiation and toxic chemicals
tween functionally-related proteins/genes that control specific aspects (Calabrese et al., 2017a; Calabrese et al., 2010; Calabrese et al., 2016b;
of (patho)physiology in a manner reminiscent of network bridging Pennisi et al., 2017). These hormetic-dose responses are independent of
factors in mathematical small-world network theory (Watts and the biological model, cell type, endpoint, and chemical class/physical
Strogatz, 1998). Identifying and therapeutically targeting these hubs, agents and mechanisms. They are therefore highly generalizable and a
before the onset of systemic age-related damage, may represent a novel fundamental evolutionary strategy. In addition, the phenomenon of
and highly effective mechanism for treating age-related degeneration. pre-conditioning and post-conditioning have also been shown to con-
Research has identified the G protein-coupled receptor kinase inter- form to the quantitative features of the hormetic dose response and are
acting protein 2 (GIT2) as a potential ‘hub’ molecule that controls the now considered to be manifestations of hormesis (Calabrese et al.,
ageing process by regulating the rate of damage accumulation, in the 2017a).
form of oxidative stress and DNA damage, across the lifespan
(Chadwick et al., 2012, 2010; Lu et al., 2015; Martin et al., 2015; 3.4. Non-coding RNAs and miRNAs
Siddiqui et al., 2017). GIT2 acts as a molecular bridge between diverse
physiological processes that are interconnected in the ageing process. Coding transcripts responsible for protein expression make up less
Therefore, therapeutic control of this keystone factor likely represents than three per cent of the human genome. Recently, it has been found
an important way forward for the treatment of age-dependent dis- that around 80 per cent of the human genome is transcribed into non-
orders, such as AD and others related to neurodegeneration. coding RNAs, with a substantial amount of these being functionally
active RNAs. Non-coding RNAs are divided into 2 groups called small
3.3. Oxidative stress, inflammation and mitochondria non-coding RNAs (e.g. microRNAs) and long non-coding RNAs (e.g.
IncRNAs) (An integrated encyclopedia of DNA elements in the human
The pharmacological manipulation of cellular-stress pathways is genome, 2012; Uchida and Dimmeler, 2015). Non-coding RNAs play an
emerging as a viable approach to treating certain neurologic diseases important role in regulating a large number of cellular functions and
such as AD, or psychiatric disorders such as schizophrenia (Calabrese physiological processes. In the brain, they have been shown to play a
et al., 2016a; Calabrese et al., 2017b). For instance, increased oxidative role in the regulation of different brain functions, such as neural stem
stress can damage mitochondrial proteins and has been implicated as a cell maintenance, neurogenesis and gliogenesis, brain patterning, sy-
contributory factor to AD pathogenesis. To adapt to environmental naptic and stress responses, and neural plasticity (Huang et al., 2017).
changes and survive different types of injuries, brain cells have evolved Studies on ageing processes, as well as the characterization of various
networks of responses that detect and control diverse forms of stress. neurodegenerative diseases using different genetic models (e.g. yeast,
Consistent with this notion, integrated survival responses exist in the fly, mouse, and human systems), have demonstrated the role of these
brain, which are under control of redox-dependent genes, called vita- non-coding RNAs on brain function/dysfunction (Szafranski et al.,
genes, including heat shock proteins (Hsps), sirtuins, thioredoxin, and 2015), implicating a variety of RNA-regulatory processes. For example,
lipoxin A4 (LXA4) (Calabrese et al., 2011). Vitagenes network is com- R-loop formation and RNA accumulation represent mechanisms in
posed, besides those mentioned above, by genes, such as Nrf2-depen- brain ageing and neurodegeneration. Long non-coding RNAs have been
dent enzymes heme oxygenase and γ-glutamyl cysteine ligase, which suggested to regulate depression (Huang et al., 2017). MicroRNAs
sense redox perturbations, including oxidative damage, and actively (miRNAs) are an abundant class of short non-coding RNAs that regulate
operate in promoting cell survival under physiopathological conditions a variety of cellular processes through the post-transcriptional regula-
(Calabrese et al., 2011). LXA4 as an endogenously produced eicosanoid, tion of gene expression (He and Hannon, 2004). miRNAs have also been
which blocks the generations of pro-inflammatory cytokines and toxic shown to regulate processes associated with brain ageing, declining
compounds including reactive oxygen species (ROS), promotes resolu- brain function, and neurodegenerative diseases (Karnati et al., 2015).
tion of inflammation, and acts as an endogenous “breaking signal” in For instance, miRNAs have been identified as critical players in fun-
the inflammatory process. Additionally, recent evidence linking the damental brain development processes, such as neuronal differentia-
restoration of redox homeostasis by nutritional mushrooms (e.g. Cor- tion, neuronal longevity, and survival. miRNA dysfunction may trigger
iolus versicolor, Hericium erinaceus), suggests potential neuroprotective overt neuronal degeneration and neurodegenerative disease-associated
strategies in brain ageing and neurodegenerative disease aimed at in- pathways (Szafranski et al., 2015). For example, the level of two pro-
ducing the vitagene defence system mechanism (Trovato et al., teins, amyloid precursor protein (APP) and membrane-bound proteases
2016a,b). β-site APP-cleaving enzyme 1 (BACE1), which contribute to the for-
Recent studies have demonstrated that the inflammasome mod- mation of amyloid plaques in AD, are controlled by miRNAs (Salta and
ulates neuro-inflammatory processes at the initial stage, followed by a De Strooper, 2012). AD is characterized by the accumulation of amyloid
secondary cascade of events including oxidative stress (Freeman and plaques in the brain, consisting of an aggregated form of amyloid β-
Ting, 2016). Inflammasomes are multiprotein complexes assembled in peptide derived from sequential amyloidogenic processing of the APP
response to infection, cell damage, or environmental stress. The AIM2 by BACE1 and γ-secretase (Toh and Gleeson, 2016). In the adult mouse
inflammasome is activated by cytosolic DNA and in addition, it has brain, deletion of Dicer (an enzyme responsible for the final maturation
recently been demonstrated that mitochondria represent major sources of precursor miRNA (Shukla et al., 2011)), resulted in neurodegenera-
of Damage-Associated Molecular patterns (DAMPs) capable of trig- tion and tau pathology (Hébert et al., 2010). In PD, reduced expression
gering neuro-inflammatory responses, with resulting apoptosis and of miR-34b and miR-34c has been identified in the affected brain areas
pyroptosis (highly inflammatory form of programmed cell death). In- including the frontal cortex, cerebellum, substantia nigra, and amyg-
appropriate recognition of cytosolic DNA by AIM2 contributes to the dala. The reduction of these miRNA molecules is thought to cause mi-
development of a number of autoimmune and inflammatory diseases tochondrial dysfunction and oxidative stress, as well as the lower ex-
and neurodegenerative disorders. The pharmacological modulation of pression of DJ1 and Parkin proteins related to both familial and

S. Miquel et al. Ageing Research Reviews 42 (2018) 40–55

idiopathic cases (Minones-Moyano et al., 2011). miR-9miR-9* expres- and eicosapentaenoic acid (EPA)) consumption and prevalence of
sion is reduced with disease progression of HD (Packer et al., 2008), cognitive decline has been found in humans, with decreased levels of n-
leading to an increase in REST protein, and consequently suppression of 3 PUFA in the blood and the brain of aged patients with cognitive
neuronal gene expression that contributes to neuropathology (Junn and impairment (Bazinet and Laye, 2014). Chronic inflammation in the
Mouradian, 2012). miR-132 was shown to maintain neurite growth by brain together with microglia activation can lead to neuronal damage.
inhibiting its mRNA target, p250GAP (Vo et al., 2005). In mouse models Recent evidence indicates that n-3 PUFA and flavonoids play a role in
of HD and post-mortem tissue of HD patients, miR-132 was found to be preventing neuroinflammation and modulating age-related memory
significantly lower, providing support for the abnormal regulation of decline (Vauzour et al., 2015). They act as potent anti-inflammatory
neurite growth (Dantzer et al., 2008). Furthermore, miRNAs dysfunc- bioactives, resolving inflammation through several pathways, i.e. sup-
tion has been implicated downstream of some key RNA-binding pro- pressing the activation of microglia through the down-regulation of
teins such as TDP43. As mentioned earlier, TDP43 is linked to dementia cytokine expression and the modulation of signalling pathways in-
and amyotrophic lateral sclerosis. TDP43 may additionally act as a volved in the resolution of inflammation (Vauzour et al., 2015). n-3
regulator of miRNA biogenesis and function, and this appears as an PUFA also harvest protective effects indirectly, through the synthesis of
important pathogenic mechanism in neurodegenerative diseases bioactive mediators with pro-resolutive activities such as resolvins
(Szafranski et al., 2015). (Vauzour et al., 2015). Resolvins (D1 and E1) derived from DHA and
EPA are promising therapeutic compounds to target brain inflammation
4. Nutritional strategies to modulate mechanisms and (Rey et al., 2016).
vulnerabilities to poor cognitive ageing
4.2. Amino acids
The rate and severity of cognitive decline during normal ageing can
be attenuated by a wide variety of factors, such as improved nutrition Tyrosine is a conditionally-essential, large, neutral amino-acid,
and appropriate dietary supplementation (Swaminathan and Jicha, which is the precursor of the catecholamines (e.g. dopamine and nor-
2014). Some of those nutrients or dietary interventions involved are adrenaline). Tyrosine is naturally present in protein-rich foods, such as
detailed below. meat, fish, dairy products, but also in nuts, seeds, and beans. Oral ad-
ministration of tyrosine leads to increased catecholamine synthesis,
4.1. n-3 PUFAs especially dopamine (Growdon and Melamed, 1980; McTavish et al.,
1999; Scally et al., 1977). Dopamine is important for cognitive control
Prospective observational studies indicate that Mediterranean-like functions (for a review, see (Cools and D’Esposito, 2011; van
diets (i.e. diets high in fish, olive oil, nuts and vegetables) may postpone Schouwenburg et al., 2010), including working memory and response
the onset of dementia (Martínez-Lapiscina et al., 2013; Scarmeas et al., inhibition. Tyrosine administration increased cognitive control func-
2006; Sofi et al., 2008). Omega-3 polyunsaturated fatty acids (n-3 tions in cognitively healthy, young adults, both under stress (Deijen
PUFA) may have primary preventive effects on dementia, although et al., 1999; Deijen and Orlebeke, 1994; Mahoney et al., 2007; Shurtleff
mainly positive observational studies are so far not confirmed by in- et al., 1994; Thomas et al., 1999), which accelerates catecholamine
tervention studies (Mazereeuw et al., 2012; Morris et al., 2005; van de metabolism (Bliss et al., 1968) and in normal circumstances (Colzato
Rest et al., 2009; Zhang et al., 2016). n-3 PUFA may have secondary et al., 2014, 2013; Steenbergen et al., 2015). Ageing is accompanied by
preventive effects when given to older subjects with early memory a decline in dopamine signalling (Bäckman et al., 2011, 2006) and
disturbances (Freund-Levi et al., 2006). Nutrition most likely cannot associated impairments in cognitive control, such as working memory
affect AD or other dementia types when the conditions are already es- (Gazzaley et al., 2005; Li and Rieckmann, 2014; Turner and Spreng,
tablished (Burckhardt et al., 2016). Thus, healthy nutrition like Medi- 2012) and response inhibition (Bedard et al., 2002; Bloemendaal et al.,
terranean-like dietary patterns or n-3 PUFA may be able to prevent or 2016; Van de Laar et al., 2012). Under which circumstances tyrosine
postpone disease processes, but may not be able to reverse the disease would increase cognitive control functions in cognitively healthy older
process or to dissolve the pathogenic deposited substances in the brain. adults is still to be established. However, it seems likely that tyrosine
A n-3 PUFA enriched supplement or oral nutrition support with ba- administration would be especially beneficial in the case of neuroin-
lanced content of macronutrients for energy as well as of micronutrients flammation. Tyrosine is the precursor of L-Dopa in the dopamine
like vitamins, minerals, and trace elements may positively affect weight synthesis pathway. The synthesis of L-Dopa from tyrosine depends on
and appetite in patients with mild to moderate AD and other cognitive tyrosine hydroxylase and its cofactor tetrahydrobiopterin (BH4). Re-
diseases, and will maintain nutritional status and contribute to better active Oxygen Species (ROS) that are generated downstream of in-
general functionality (Allen et al., 2013; Irving et al., 2009). In animal flammatory activity can inactivate BH4 (Neurauter et al., 2008),
models of AD, long-term fatty acid supplementation decreases the n-6/ thereby affecting dopamine synthesis. Studies in humans and non-
n-3 ratio and improves cognitive function, suggesting that the duration human primates have indeed shown inflammation-associated reduc-
of supplementation may be a reason why no effects of n-3 PUFA sup- tions in dopamine signalling (Felger and Treadway, 2017). Adminis-
plementation could be observed in patients with moderate or advanced tration of the dopamine precursor L-Dopa reversed the detrimental ef-
AD (Hooijmans et al., 2012). Perspectives for future human studies are fect of pro-inflammatory cytokine IFN-α on striatal dopamine release in
thus to clearly define the population that will be subjected to the in- non-human primates (Felger et al., 2015). Increasing L-Dopa’s pre-
tervention trial and to include enough participants, as enabling a long cursor tyrosine, by dietary supplementation, might similarly be ad-
enough duration of the intervention (Sydenham et al., 2012). vantageous in reducing the negative effects of inflammation-associated
Experimental studies provide insights into feasible mechanisms for inactivation of BH4 on dopamine synthesis efficiency.
the potential beneficial n-3 PUFA effects on cognitive functions Large neutral amino-acid precursors of neurotransmitters, such as
(Chakraborty et al., 2017; Hooijmans et al., 2012). Docosahexaenoic tyrosine and its precursor phenylalanine can also be synthesized by gut
acid (DHA), representing 10–20% of the brain cells lipids, is known to microbiota (Clayton, 2012; Gertsman et al., 2015). These microbial-
play multi-functional roles in brain health and diseases. DHA and produced precursors might be absorbed through the intestinal epithe-
PUFAs regulate several processes within the brain via their mediators, lium, enter the portal circulation, cross the blood-brain barrier, and
such as neurotransmission, cell survival, and neuroinflammation, and influence host catecholamine synthesis (Lyte, 2013). Indeed, a recent
thereby mood and cognition (Bazinet and Laye, 2014; Sun et al., 2017). study in young adults demonstrated that predicted microbial synthesis
In animal models, decreased n-3 PUFA alter emotional behaviour and of phenylalanine was associated with altered neural reward processing
memory, and an inverse relation between fish-derived n-3 PUFA (DHA in the ventral striatum (typically dependent on dopamine processing)

S. Miquel et al. Ageing Research Reviews 42 (2018) 40–55

(Aarts et al., 2017). Interactions between dietary catecholamine pre- (Scholey et al., 2010). This potentially beneficial effect of polyphenol
cursors and microbial neurotransmitter precursor synthesis should be rich-food on brain function may be linked to increased blood flow in the
taken into account when considering the beneficial effects of dietary brain (Lamport et al., 2015). Nutritional intervention with high-fla-
phenylalanine and tyrosine in aging. vanol drinks for three months has been shown to significantly increase
The essential, large, neutral amino-acid, tryptophan, is the pre- cerebral blood volume in the dentate gyrus area of the hippocampus
cursor of serotonin (and melatonin). Tryptophan is found in nearly all and significantly enhance performance (reaction time) on a pattern
protein-containing foods. Dietary intake of tryptophan influences ser- separation task (Brickman et al., 2014). Pattern separation tests, which
otonin synthesis and release in the brain (Fernstrom, 1983). Serotonin test the ability to distinguish between previously presented pictures and
is involved in a variety of neurocognitive functions, including sensor- very similar ones, can be directly related to activity in the dentate
imotor function, learning, and memory (Muller and Jacobs, 2009). gyrus, an area where neurogenesis occurs (Bakker et al., 2008).
Tryptophan administration in young adults has been shown to improve Therefore, age-related decline in the ability to discriminate closely si-
memory (for a review, see van de Rest et al., 2013). Similar to tyrosine, milar pictures reflects reduced activity in the dentate gyrus (Toner
studies of tryptophan administration in cognitively healthy older adults et al., 2009; Wesnes, 2010). Importantly, deficits in this task have been
are mostly lacking, even though serotonin signalling also declines with linked to the genotype associated with susceptibility to AD as well as
ageing (McEntee and Crook, 1991). Interestingly, the above-mentioned cerebrospinal levels of Aβ42 (Wesnes et al., 2014).
mechanism of ROS-induced inactivation of BH4 is relevant for ser- Even though data exists revealing the positive effect of polyphenols
otonin synthesis as well, as tryptophan hydroxylase,needed for con- on brain and vascular function, the mechanisms of action underlying
version of tryptophan into 5-Hydroxy-tryptophan (5-HTP), which in their beneficial effects appear to be complex and are not fully under-
turn is converted into serotonin (5-Hydroxy-tryptamine, 5-HT), is de- stood yet (Field et al., 2011; Scholey et al., 2010; Vauzour et al., 2017).
pendent on cofactor BH4 also. However, there is another important A large number of in vitro studies exist showing the capacity of poly-
inflammation-related mechanism associated with tryptophan. Specifi- phenols to modulate not only the expression of genes, but also ex-
cally, pro-inflammatory cytokines, such as IFN-γ, IL-1β, and TNF-α pression of miRNA and proteins, and induce epigenetic modifications
catalyse the conversion of tryptophan into kynurenine at the expense of (Claude et al., 2014; Krga et al., 2016; Mandel et al., 2008; Schroeter
serotonin production, by inducing the expression of indoleamine 2,3- et al., 2007, 2001; Vauzour et al., 2007). Most of these studies have
dioxygenase (IDO) (O’Connor et al., 2009a, 2009b). Subsequently, ky- been performed using native forms of polyphenols (forms found in
nurenine is metabolized by microglia into, amongst others, quinolinic fruits) at high concentrations. However, the bioavailability of ingested
acid, a neurotoxic that generates ROS. Indeed, the kynurenine/trypto- polyphenols is generally low and most often the absorbed forms are not
phan ratio in blood is increased in AD and related to decreased cogni- the native compounds (Bohn et al., 2015). The forms present in the
tive performance (Widner et al., 2000). Kynurenine can also be con- circulation that can reach target tissues result from extensive metabo-
verted to kynurenine acid with neuroprotective properties. However, in lism involving both enzymatic activities of the gut microbiota (Tomas-
rats, tryptophan administration increased brain levels of the neurotoxic Barberan et al., 2016; Williamson and Clifford, 2017) and endogenous
quinolinic acid to a much greater extent than levels of the neuropro- conjugative enzymes (Espin et al., 2017). Plasma metabolites of poly-
tetive kynurenine acid and even that of serotonin (Freese et al., 1990). phenols are mainly either conjugated derivatives, in glucuronidated-,
Thus, given the potential conversion to kynurenine and quinolinic acid, sulphated-, and methylated-forms, or metabolites of microbial origins
dietary supplementation of tryptophan should be done with caution. On found at concentrations in nano to few microM ranges. Taken together,
the other hand, commensal bacteria can catabolize dietary tryptophan knowledge of the molecular and cellular mechanisms of action is in-
to indole, indole-3-aldehyde, and indole-3-propionate, with potential complete. Further studies are needed to enhance our knowledge of the
anti-inflammatory effects (for a review, see (Zhang and Davies, 2016)). mechanisms linking these bioactives with health benefits.
However, given that the gut microbiome is affected by aging, as dis-
cussed above, the beneficial effects of tryptophan consumption in this 4.4. Multi-nutrient interventions
regard still needs to be elucidated.
Single nutrient interventions have generally shown no cognitive
4.3. Polyphenols benefit in mild cognitive impairment (MCI) and AD (Aisen et al., 2008;
Dysken et al., 2014; Freund-Levi et al., 2006; Galasko et al., 2012;
Polyphenols are micro-constituents of plant-based foods, which are McMahon et al., 2006; Petersen et al., 2005; Quinn et al., 2010). It is
widely distributed in the human diet. The main dietary sources of likely that the potency of single nutrients is insufficient to achieve a
polyphenol intake are fruits and fruit-derived products (Pérez-Jiménez clinically relevant benefit. A hypothesis-driven specific nutrient com-
et al., 2010), which is a main constituent of the Mediterranean-style bination (called Fortasyn Connect) of uridine, docosahexaenoic acid,
diet. Adherence to a Mediterranean diet is associated with slower eicosapentaenoic acid, choline, phospholipids, folic acid, vitamins B12,
cognitive decline, and reduced incidence of dementia and AD (Vauzour B6, C, E, and selenium has been designed to ameliorate synapse loss,
et al., 2017). Epidemiological studies suggest an inverse relationship synaptic dysfunction, and other pathological pathways affected in AD
between the intake of different classes of polyphenols and the risk of by addressing distinct nutritional needs believed to be present in these
different age-related diseases, such as cardiovascular diseases, cancer, patients (Van Wijk et al., 2014). This specific nutrient combination is
or metabolic disorders (Vauzour et al., 2010). The potential of these based on the notion that cognitive decline in MCI and AD is a result of
compounds to prevent neurodegenerative disorders is also documented loss of synapses (de Wilde et al., 2016). Formation of synapses is rate-
in several animal studies. For example, it has been shown that diets limited by specific nutrients that are the precursors for the formation of
supplemented with blueberry (a fruit rich in anthocyanins) improve the neuronal membranes and act by enhancing the substrate-saturation of
performance of aged animals in spatial working memory tasks the enzymes that catalyze the rate-limiting steps of membrane phos-
(Williams et al., 2008). Several clinical studies have also demonstrated pholipid synthesis through the Kennedy Pathway (Wurtman et al.,
potential beneficial effects of polyphenol-rich fruit on brain function 2009). Beneficial and synergistic effects of the specific nutrient com-
(Khalid et al., 2017; Miller et al., 2017; Valls-Pedret et al., 2012). One bination of precursors and cofactors of neuronal membrane formation
study revealed that consumption of flavanone-rich orange juice is have been demonstrated in several animal models by various groups
beneficial for cognitive function in cognitively healthy older adults with and on several biological phenomena that are indicative of increased
no significant effects on mood or blood pressure (Kean et al., 2015), synapse formation and function and other pathological processes that
while consumption of cocoa flavanols beneficially affects cognitive are characteristic of AD, and published in over 30 peer-reviewed pub-
performance and mood during highly effortful cognitive processing lications (Cansev et al., 2015; Janickova et al., 2015; Van Wijk et al.,

S. Miquel et al. Ageing Research Reviews 42 (2018) 40–55

2014; Wiesmann et al., 2016; Wurtman et al., 2009). These results Other European multi-domain interventions offer some additional
suggest that people with AD pathology may benefit from increased insights. The Prevention of Dementia by Intensive Vascular care
intake of these nutrients. Importantly, meta-analyses show that the le- (preDIVA) trial tested a 6-year multi-domain vascular intervention in-
vels of these nutrients in circulation and in the brain are lower in AD cluding dietary advice in 3526 older individuals (age 70–78 years) from
than in non-AD controls (Lopes Da Silva et al., 2014). Collectively, these general practices in the Netherlands (Moll van Charante et al., 2016).
insights indicate that the nutritional need for these nutrients is higher in The control group received usual care. The intervention did not result in
AD and led to the development of Souvenaid, a medical food for early a reduced incidence of all-cause dementia in this unselected sample of
AD comprising this specific nutrient combination (Van Wijk et al., older people in a general practice setting with high standards of usual
2014). The clinical efficacy of Souvenaid was tested in a clinical trial care. However, some benefits on dementia incidence were noted in at-
program, with trials in AD patients at various stages of AD, and on risk subgroups (e.g. participants with untreated hypertension at base-
clinical outcomes as well as neuroimaging measures. Studies in drug- line who adhered to the intervention).
naïve mild AD showed that the intervention increased magnetic re- The Multi-domain Alzheimer Preventive Trial (MAPT) study was
sonance spectroscopy measures of brain neuronal membrane synthesis designed to test whether a combination of nutritional counselling,
(Rijpma et al., 2017) and electroencephalography (EEG) measures of physical exercise, and cognitive stimulation, together with n-3 PUFA
functional connectivity and functional brain network organisation (De supplementation, is effective in slowing cognitive decline in frail older
Waal et al., 2014; Scheltens et al., 2012); while in prodromal AD, a 2- adults at risk of cognitive decline (Andrieu et al., 2017; Vellas et al.,
year Randomised Control Trial (RCT) showed reduced hippocampal 2014). The MAPT trial is the first largest and longest multi-domain
atrophy (Soininen et al., 2017). Studies in drug-naïve mild AD showed a preventive trial relevant to cognitive decline in older adults with sub-
significant benefit on memory performance (Rikkert et al., 2015; jective memory complaints, and is easily implementable in the general
Scheltens et al., 2012, 2010), the primary endpoint in these RCTs and population. This multi-domain intervention brings some hope regarding
the most pronounced clinical symptom of early AD. More recently, an long-term effects of a multi-factorial approach to prevent development
independent EU funded 2-year RCT in prodromal AD reported favour- of impaired cognition (Andrieu et al., 2017; Vellas et al., 2014).
able effects on memory and a clinical relevant combined measure of Nevertheless, additional trials are needed to confirm these observa-
cognition and function (CDR-SB) (Soininen et al., 2017). In conclusion, tions.
mechanistic studies on this specific nutrient combination together with Findings from the FINGER, preDIVA and MAPT trials thus suggest
the Souvenaid clinical trials in AD show consistent effects on brain that preventive interventions may need to be adequately targeted to at-
function, metabolism, structure, and measures of cognition and func- risk populations in order to be most effective. Interventions may also
tion that corroborate the working mechanism of the specific interven- need to be sufficiently intensive for benefits to become apparent. In
tion (De Waal et al., 2014; Hartmann et al., 2014; Rijpma et al., 2017; conclusion, the various research innovations described above will en-
Scheltens et al., 2012, 2010; Soininen et al., 2017). In addition, these able trials to be conducted on scales which were not previously pos-
studies together support the notion that clinical relevant benefit on sible, with numerous treatment arms to allow optimal combinations of
brain function in ageing can be achieved by a hypothesis-driven nu- various interventions to be established for multiple groups of in-
trient combination that amplifies the potency of single compounds (von dividuals having shared genotypes as well as phenotypes. This field has
Arnim et al., 2010). now entered the ‘big data’ era, which will enable research questions to
be addressed that previously were not feasible even to propose.
5. Application and impact
5.2. Relevance for public health and regulatory implications
5.1. Multi-domain interventions
The increased ageing population and rise in cognitive decline ex-
Epidemiological studies demonstrate that links exist between nu- pectedly impacts public health. Future outcomes relevant for public
trition, physical activity, and cognitive and social stimulation that help health include development of health claims related to improvement of
to improve brain health. As prevention has been advocated as an ef- cognitive function. For instance a claim on ‘DHA and improvement of
fective way to reduce the burden of AD (Norton et al., 2014), multi- memory function’ was recently approved by EFSA (EFSA Panel on
domain interventions seem therefore appropriate to target the multiple Dietetic Products, 2016). A claim for ‘cognitive function’ requires evi-
factors involved in cognition and ageing. The Finnish Geriatric Inter- dence for an effect involving several specific domains and outcomes,
vention Study to Prevent Cognitive Impairment and Disability (FINGER, emphasising the multi-factorial aspect of the ageing process. Further-
NCT01041989) was a 2-year multicentre randomized controlled trial more, some EU initiatives highlight the importance of health and nu-
with 1260 participants aged 60–77 years recruited from previous po- trition in the centre of attention. Besides the huge socio-economic im-
pulation-based survey cohorts. The multi-domain intervention included pact of healthy and most notably, pathological ageing, the increasing
four components: nutritional guidance, physical exercise, cognitive relevance of global public health highlights the growing interest in
training and social activities, and management of vascular/metabolic understanding cognitive function and healthy ageing, with nutrition as
risk factors. The control group received regular health advice. The spearhead.
primary outcome after two years was change in cognition (neu- In respect of pathological ageing, research interest and regulatory
ropsychological test battery, NTB z-score). FINGER is the first ‘proof-of- requirements are moving towards studies in cognitively healthy in-
concept’ trial showing that a multi-domain lifestyle intervention had dividuals, either carrying specific biomarkers of pathological ageing or
significant beneficial effects on cognition in an at-risk older general in those ageing in the absence of disease. This supports the hypothesis
population (Ngandu et al., 2015). Significant intervention effects were that factors such as diet will help maintain healthy ageing and is crucial
also found for several secondary outcomes (e.g. dietary habits, body to help prevent or delay the onset of neurodegenerative disorders
mass index, physical activity, quality of life, and disability). Key de- (Harvey et al., 2017; Kozauer and Katz, 2013; Roses et al., 2013; Small
terminants of intervention success were: the combination of group ac- and Vorgan, 2012; Sperling et al., 2011; Whitehouse, 2014).
tivities with individualized, concrete counselling (facilitating both
personal and within-group motivation and support for healthy lifestyle 6. Conclusion and future directions
changes), knowledgeable staff, providing positive feedback, and inclu-
sion of community support. FINGER showed that a multi-domain life- The ILSI Europe workshop ‘Nutrition for the ageing brain: func-
style intervention in at-risk older individuals is feasible and safe. tional aspects and strategies’ and the present paper highlight the value
Compliance was high, and participants’ experiences were very positive. of combining studies of cognitive ageing with well-designed studies

S. Miquel et al. Ageing Research Reviews 42 (2018) 40–55

investigating how dietary interventions can be a strategy to target the factors towards a rejuvenating milieu are potentially effective means to
mechanisms of ageing. However, to advance, future research in this promote healthy cognitive ageing by enhancing stem cell function and
field may need to adopt a longitudinal approach to ensure the effect of neurogenesis (Murphy and Thuret, 2015). There is currently a real need
early-life stress is adequately measured. Interventions may also need to for dietary human interventions coupled with in vitro assays involving
be imposed prior to the onset of pathological cognitive ageing. immortalized human stem-cell lines, and neurogenesis-dependent cog-
Researchers will need to consider factors, such as epigenetic changes or nitive tasks such as pattern separation, which targets the dentate gyrus
gut microbiome diversity in the ageing process. Innovation in research (Bakker et al., 2008). Although the dentate gyrus is suggested to reg-
and the development of new technologies will enable trials to be con- ulate neurogenesis, the only information in humans supporting this is
ducted on scales which have not previously been possible, with nu- based upon blood perfusion using fMRI (Brickman et al., 2014). There
merous treatment arms to allow optimal combinations of various in- are currently no real ways of measuring neurogenesis in human brain
terventions to be established for multiple groups of individuals that tissue and most of the information gathered to date is derived from
have shared genotypes as well as phenotypes. animal studies.
Longitudinal monitoring of cognition across the lifespan is essential In the case of polyphenols, it is important to perform clinical trials
for effective dementia prevention. Integrative approaches are required using well-defined controls to identify a proper role of compounds
that are sensitive to the synergistic action of various risk and protective (such as flavanols) on brain function. Further in vitro studies will be
factors and their possible common pathways. One major question for necessary, together with pre-clinical studies, to identify as precisely as
the field is whether these various lifestyle choices all compete for a possible the cellular and molecular mechanisms of action of poly-
limited opportunity to enhance cognitive function, or whether the ef- phenols. Future studies should take into account the multiple targets
fects could be additive or even synergistic. Individual variations in risk and multiple modes of action of polyphenols. These studies should si-
profiles for dementia must also be taken into account, as different multaneously investigate the impact of polyphenols on the of expres-
lifestyle choices may have different contributions to the overall risk in sion of genes, non-coding RNAs, proteins, and other regulators of cell
different people. Cognitive function is a broad topic and it would be function, such as cell signalling pathways or epigenetic modifications to
advantageous if the research community could agree on which cogni- identify molecular mechanism(s) of action. For in vitro studies, circu-
tive tests to use as outcome measures. As Matthews et al. (2013) argue, lating forms of polyphenol metabolites at physiologically relevant
whether prevalence rates will continue to rise, ‘will probably depend on concentrations should be used.
whether further improvements in primary prevention and effective Future studies should also assess the peripheral and central me-
health care for disorders that increase the risk of dementia can be chanisms underlying potential age-related differences in tyrosine or
achieved, including addressing inequalities’ (Matthews et al., 2013). tryptophan effects on cognition in placebo-controlled designs, with
The aetiologies of dementia and age-related cognitive decline are both young and older adults. When assessing the effects of age, long-
multi-factorial, therefore, it is likely that multi-dimensional interven- itudinal designs are preferred, as cross-sectional designs cannot easily
tions will be required to effectively delay dementia onset. Large-scale control for between-subject differences other than age. Amino-acid
dementia prevention studies are essential to address the current gaps in administration studies in older adults should also use longer supple-
knowledge and accelerate advances through multifactorial approaches. mentation designs, as effects of auto-regulation of monoamine synthesis
In addition, it is also crucial to widen the scope of our current concept might differ for acute administration with high doses versus supple-
of potential patho-mechanisms that contribute to cognitive decline, mentation with continuous lower doses.
both at the level of the central nervous system and also peripheral In the case of fatty acids, it is important to take into account the
tissues. A multifaceted approach to identify new viable strategies is regular baseline fish or n-3 PUFA intake, or baseline serum concentra-
vital for the creation of new and effective therapeutics. International tions of DHA as well as EPA. Recent studies demonstrated that higher
collaborations within extensive networks, including partners from both levels of DHA/EPA may help protect against the development of de-
academia and industry, are already starting to be established. Some key mentia (Ammann et al., 2017). If the intake or the serum levels are
issues for future dementia prevention research are: the harmonisation already sufficient, further beneficial effects of fatty acid supplementa-
and optimisation of methodologies for multinational and multi-domain tion is not to be expected. This would be like performing a study on
prevention trials across the entire spectrum of cognitive impairment blood pressure medication without knowing the baseline blood pressure
and AD, international sharing of expertise and data, rethinking pre- and also providing normotensive subjects with the test medication!
vention trials (e.g. adaptive designs, inclusion of e-health components, Most of the clinical trials recruit patients with high DHA/EPA baseline
combining non-pharmacological and pharmacological approaches to values and it is therefore recommended to include only subjects with
prevention), and learning from experiences with prevention research in low intake of fish or low levels of DHA/EPA in the intervention studies,
other fields (Geerts et al., 2016). even though a threshold needs to be defined.
The longitudinal epigenetic characterisation of population sub- Priorities for future studies are to clearly define the population that
groups, which follow a specific diet for many years, may also yield will participate in the intervention trial. Proof of concept studies are
useful information on transient versus persistent epigenetic changes/ needed to design proper RCTs with sufficient power. Also, dose aspect is
epigenetic ageing in the presence/absence of specific diets (e.g. vege- also a disadvantage, as many of the animal studies investigating me-
tarian, Mediterranean, vegan, etc.) and information related to other chanisms are supra-physiological and not achievable in humans
lifestyle factors (e.g. regularity and intensity of exercise). Such studies without risk of toxicity, e.g. green tea catechins producing hepato-
should evaluate the separate and interactive effects of factors, such as toxicity at 500 mg/day (Isomura et al., 2016).
nutrition and physical exercise on epigenetic modification. Suitable Research suggests it is possible to amplify the potency of nutrient
approaches might include the development of mobile phone applica- intervention by combining nutrients that work synergistically to ensure
tions to measure health and diet/physical exercise. Integrated data the neuroprotective potential of nutrition is fully leveraged. The
analysis pipelines should be developed to explore epigenetic bio- blending of nutrients should be hypothesis driven and based on the
markers in saliva, blood, cerebrospinal fluid, and cognitive imaging specific contribution of each nutrient to the targeted biological pathway
data. (s) that underlie cognitive effects. Therefore, future research should aim
The ways that changes in the levels of circulating factors (e.g. to: 1) increase understanding of the role of specific nutrients on bio-
Insulin Growth Factor 2 (IGF2) or the Growth and Differentiation logical pathways that are relevant to cognitive ageing, 2) design and
Factor 11(GDF11)) facilitate age- and diet-induced effects on stem cell validate nutrient combinations to target mechanisms of cognitive
function, neurogenesis, and brain function need to be identified and ageing, 3) validate multi-nutrient combinations in well-designed clin-
investigated further. Dietary interventions that tip the balance of ical studies, and 4) transfer knowledge of the role of nutrition for

S. Miquel et al. Ageing Research Reviews 42 (2018) 40–55

cognitive health to recommendations for public health. Nat. Rev. Neurosci. 16, 332–344. http://dx.doi.org/10.1038/nrn3818.
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pathway in ageing: focus on the related mechanisms in age-related diseases. Ageing
Disclosure Res. Rev. 29, 50–65. http://dx.doi.org/10.1016/j.arr.2016.06.004.
Barberger-Gateau, P., 2014. Nutrition and brain aging: how can we move ahead? Eur. J.
The workshop ‘Nutrition for the Ageing Brain: Functional Aspects Clin. Nutr. 68, 1245–1249.
Bazinet, R.P., Laye, S., 2014. Polyunsaturated fatty acids and their metabolites in brain
and Strategies’ was organized with funds from the ILSI Europe Nutrition function and disease. Nat. Rev. Neurosci. 15, 771–785.
and Mental Performance Task Force. Industry members of this task Bedard, A.C., Nichols, S., Barbosa, J.A., Schachar, R., Logan, G.D., Tannock, R., 2002. The
force are listed on the ILSI Europe website at www.ilsi.eu. For further development of selective inhibitory control across the life span. Dev. Neuropsychol.
21, 93–111.
information about ILSI Europe, please email or call +32 2 771 00 14. Bendiske, J., Bahr, B.A., 2003. Lysosomal activation is a compensatory response against
This review was prepared taken into account the presentations at the protein accumulation and associated synaptopathogenesis − an approach for slowing
workshop mentioned in the abstract and was conducted by an expert Alzheimer disease? J. Neuropathol. Exp. Neurol. 62, 451–463.
Bendiske, J., Caba, E., Brown, Q.B., Bahr, B.A., 2002. Intracellular deposition, micro-
group of ILSI Europe. This publication was coordinated by Dr Lucie
tubule destabilization, and transport failure: an early pathogenic cascade leading to
Geurts, Scientific Project Manager at ILSI Europe. The opinions ex- synaptic decline. J. Neuropathol. Exp. Neurol. 61, 640–650.
pressed herein and the conclusions of this article do not necessarily Benton, D., 2010. The influence of dietary status on the cognitive performance of chil-
represent either the views of ILSI Europe or those of its member com- dren. Mol. Nutr. Food Res. 54, 457–470. http://dx.doi.org/10.1002/mnfr.
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